This variant is predicted to cause hereditary spastic paraplegia (paraplegin type) in a recessive manner. Other downstream frameshift mutations in this gene have been implicated in causing the disease. Age of onset is usually in adulthood (~25 years of age), and is characterized by progressive bilateral lower limb weakness and spasticity.

Reported by several contributors to ClinVar as causing spastic paraplegia in a recessive manner. The variant is very common, and for homozygous individuals it’s possible that penetrance is low and/or the disease is mild and undiagnosed.

The SPG7 gene (spastic paraplegia 7) encodes the mitochondrial protein paraplegin. Mutations in this gene are associated with hereditary spastic paraplegia (HSP), which is characterized by progressive stiffness and weakness in the lower limbs. The gene is located on Chromosome 16 and consists of 17 exons spanning 52kb. This is the only gene in which mutations are known to cause hereditary spastic paraplegia. Alleles are inherited in an autosomal recessive manner. The R688Q mutation is a single nucleotide polymorphism at exon 15. The polymorphism changes the ancestral allele, G, to an A at base pair 2063. This allele is also known as rs12960, which was shown to be associated with toxicity responses to chemotherapy drugs such as Docetaxel.